Dave Kashyap, Sur Inderpreet, Yan Jian, Zhang Jilin, Kaasinen Eevi, Zhong Fan, Blaas Leander, Li Xiaoze, Kharazi Shabnam, Gustafsson Charlotte, De Paepe Ayla, Månsson Robert, Taipale Jussi
Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Elife. 2017 Jun 6;6:e23382. doi: 10.7554/eLife.23382.
The gene desert upstream of the oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire upstream super-enhancer region in mice results in 50% to 80% decrease in expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.
8号染色体q24上癌基因上游的基因荒漠包含多种主要人类癌症形式的易感位点。该区域在人和小鼠之间显示出高度保守性，并且包含在肿瘤细胞中被激活的多个增强子。然而，该区域在正常发育中的作用尚未得到研究。在这里，我们表明，小鼠中整个上游超级增强子区域的538 kb缺失导致多个组织中的 表达降低50%至80%。这些小鼠是存活的，并且没有明显的表型。然而，它们对肿瘤发生具有抗性，并且从它们分离出的大多数正常细胞在培养中生长缓慢。这些结果表明，只有那些MYC活性因血清或致癌驱动突变而增加的细胞才依赖于8q24超级增强子区域，并表明靶向该元件的活性是癌症化学预防和治疗的一种有前景的策略。 （注：原文中“ expression”这里应该缺失了具体基因名称，翻译时保留了原文表述）
